Estrogens promote the development and progression of lupus, a chronic autoimmune disease affecting an estimated 1.5 million Americans, 90-95% of whom are women. Estrogens are thought to promote lupus by facilitating loss of immunologic tolerance and enhancing autoantibody production. However, the molecular pathways through which estrogens exert these effects have not been defined. Further, the relative contributions of estrogen receptors ER1 and ER2 in mediating the effects of estrogens on lupus are not presently delineated. Because both ER1 and ER2 are expressed in the immune cell lineages that contribute to lupus, the identification of the specific lineages and cell types that must express each receptor to achieve estrogen-induced enhancement of lupus remains a major unanswered question. Genetic factors control susceptibility to lupus. The action of some lupus susceptibility loci in mice is more pronounced in females, and our preliminary data indicate estrogen contributes to this gender bias. However, concrete evidence implicating estrogen receptors in modulating lupus susceptibility loci is lacking. To understand how estrogens enhance lupus, it is essential to identify the genetic factors that synergize with estrogens to promote lupus, and to determine the cell types and pathways through which estrogens augment the immune response to nuclear autoantigens. A long term goal of our laboratory is to understand how genetic and hormonal factors interact to influence lupus in order to facilitate the development of novel therapies for lupus. The objective of this application is to determine how ER1 promotes lupus in the (NZB x NZW)F1 mouse. Our central hypothesis is that ER1 acts in a B and T cell intrinsic manner to augment lupus by synergizing with genetic factors and promoting cellular processes that enhance loss of tolerance and maturation of IgG+ DNA-reactive B cells. This hypothesis is based upon our preliminary data demonstrating that ER1 deficiency in (NZB x NZW) F1 mice diminishes loss of tolerance, decreases serum interferon gamma, reduces levels of anti-dsDNA IgG antibodies and attenuates development of lupus nephritis. To test this hypothesis we will 1) Identify the lupus susceptibility loci whose activity is modulated by ER1, 2) Identify the cell lineage(s) in which ER1 must be expressed to achieve ER1-dependent acceleration of lupus and 3) Identify ER1-regulated processes that promote production of anti-DNA IgG antibodies. Our rationale for this research is that understanding how ER1 signaling promotes lupus will provide information crucial to development of therapies to prevent and treat lupus. PUBLIC HEALTH RELEVANCE: Lupus is a prevalent and life-threatening autoimmune disease that affects more than 1.5 million Americans, most of whom are women. We propose to use mouse models to determine the mechanisms through which estrogens promote lupus. These studies will provide information that is critical to the development of novel strategies, including estrogen receptor antagonists, to prevent and treat lupus.